This invention is in the field of medicinal chemistry. In particular, the invention is related to novel substituted quinazolines and analogs thereof. These compounds are antagonists of x-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) ionotropic receptors. Certain of these compounds are positive modulators of AMPA receptors. The invention also is directed to the use of novel substituted quinazolines and analogs thereof for the treatment of neuronal damage following global and focal ischemia, and for the treatment or prevention of neurodegenerative conditions, as anticonvulsants, as cognitive enhancers, and for the treatment of schizophrenia, Parkinson""s disease and myoclonus. The compounds of the invention are also useful for treatment or prevention of pain, including acute and chronic pain. The invention also is directed to a process for the preparation of the substituted quinazolines and analogs thereof.
Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed xe2x80x9cionotropic.xe2x80x9d This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonist N-methyl-D-aspartate (NMDA), xcex1-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). The second general type is the G-protein or second messenger-linked xe2x80x9cmetabotropicxe2x80x9d excitatory amino acid receptor. This second type, when activated by the agonists quisqualate, ibotenate, or trans-1-aminocyclopentane-1,3-dicarboxylic acid, leads to enhanced phosphoinositide hydrolysis in the postsynaptic cell. Both types of receptors appear not only to mediate normal synaptic connections during development, but also change in the efficiency of synaptic transmission throughout life. (Schoepp, Bockaert, and Sladeczek, Trends Pharm. Sci. 11:508 (1990); McDonald and Johnson, Brain Res. Rev. 15:41 (1990)). The excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by a mechanism known as excitotoxicity. The medical consequences of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal. (See U.S. Pat. No. 5,284,957).
Antagonists of the AMPA receptor are considered useful in treating, preventing and ameliorating a number of neurologic disorders which are due to overstimulation by the excitatory amino acids. These include acute neurologic disorders such as domoic acid poisoning; cerebral ischemia, global ischemia associated with cardiac arrest; stroke; spinal cord trauma; hypoxia; anoxia; poisoning by carbon monoxide, manganese or cyanide; hypoglycemia; mechanical trauma to the nervous system; epileptic seizures; and chronic neurologic disorders such as Huntington""s disease, neuronal injury associated with HIV and AIDS, AIDS dementia, neuropathic pain syndrome, olivopontocerebral atrophy, Parkinson""s disease, amyotrophic lateral sclerosis, mitochondrial abnormalities, Alzheimer""s disease, hepatic encephalopathy, Tourette""s syndrome, drug addiction and urinary incontinence (see Lipton and Rosenberg, N. Engl. J. Med. 330: 613-622 (1994)) and treatment or amelioration of a number of chronic neurologic disorders such as schizophrenia. AMPA receptor antagonists are also useful in treating, preventing and ameliorating acute and chronic pain, pain associated with post-therapeutic neurolgia, interstitial cystitis, osteoarthritis, spinal cord injury, cancer and diabetic neuropathy.
There is much evidence suggesting that the interaction of glutamate with membrane receptors plays a key role on many critical neurological functions such as cognition, learning and memory. Cognitive deficits likely arising from hypoactivity of glutamate receptors are known to be associated with neurodegenerative disorders such as Alzheimer""s disease. Hypoactivity of glutamate receptors also might be associated with schizophrenia. One therapeutic approach is the direct stimulation of glutamate receptors with agonists. However, this approach increases the risk of excitotoxicity and may lead to further neurodegeneration. Selective positive modulation of certain glutamate receptor subtypes would be a better approach. Therefore positive modulators of AMPA receptors are expected to be useful for the treatment or amelioration of a number of chronic neurologic disorders such as schizophrenia, Alzheimer""s disease and malnutrition and neural maldevelopment (Thomas, R. J., J. Am. Geriatr. Soc. 43. 1279-1289 (1995)). It has been shown that the AMPA receptor positive modulator BDP 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine and its derivatives enhance memory in rat (Staubli et al., Proc. Natl. Acad. Sci. 91: 777-778 (1994)). The AMPA positive modulator BDP-29 also has been shown to attenuate the amount of stereotypic rearings seen in rats after methamphetamine injection, suggesting that AMPA receptor modulators might be useful for the treatment of schizophrenia (Larson et al. Brain Res. 738, 353-356 (1996)). Furthermore, piracetam, a well known nootropic agent which is used to treat cognitive impairment in the elderly, was found to be a positive modulator of AMPA receptors (Copani et al. J. Neurochem. 58: 1199-1204 (1992)). A recent clinical study showed that piracetam was effective in treating patients with myoclonus, especially that of cortical origin (Ikeda et al. Movement Disorders 11: 691-700 (1996)). Thus, AMPA receptor positive modulators are useful in treating myoclonus.
Recent studies have shown that AMPA receptor antagonists are neuroprotective in focal and global ischemia models. The competitive AMPA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline) has been reported to be effective in preventing global and focal ischemic damage. (Sheardown et al., Science 247:571 (1990); Buchan et al., Neuroreport. 2:473 (1991); Lepeillet et al., Brain Res. 571:115 (1992)). The noncompetitive AMPA receptor antagonist GKYI 52466 (1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine-hydrochloride) has been shown to be an effective neuroprotective agent in rat global ischemia models. (Lapeillet et al., Brain Res. 571:115 (1992)). GYKI 52466 has also been shown to be an effective anticonvulsant (DeSarro et al., Eur. J. Pharmacol. 294:411 (1995)).
These studies strongly suggest that the delayed neuronal degeneration in brain ischemia involves glutamate excitotoxicity mediated at least in part by AMPA receptor activation. Thus, AMPA receptor antagonists are useful as neuroprotective agents and improve the neurological outcome of cerebral ischemia in animals. (See U.S. Pat. No. 5,284,957).
Hunter and Singh reported that 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline (NBQX), a prototypical AMPA receptor antagonist, is active in blocking animal model of acute pain (Neurosci. Lett. 174(2): 217-221 (1994)).
Sang et al., reported recently that (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid (LY2935586) was effective in blocking the sensitization in the spinal neuron that mediates capsaicin-evoked allodymia and hyperalgesia in human, (Soc. Neurosci. Abstract #401.14, 1997) a human model of chronic pain.
Anderson et. al., (J. Am. Chem. Soc. 117.12358-12359 (1995)) reported the synthesis of 5-H-2,3-benzodiazepine (LY3300164) shown below. The compound is said to be a noncompetitive antagonist of AMPA receptors with anticonvulsant activity. 
Pelletier el. al. (J. Med. Chem. 39: 343-346 (1996)) reported recently substituted 1,2-dihydrophthalazines as noncompetitive inhibitors of the AMPA receptor. For example, the compound shown below is said to be active as an anticonvulsant in the maximal electroshock model. 
A group of 1-alkyl-4-aryl-2(1H)-quinazolinones and quinazolinethiones were reported to have antiinflammatory activity (J. Med. Chem. 16: 1237-1245 (1973)). 
Where R1 is H and alkyls such as Me, Et, i-Pr; R2-R5 are independently H, Me or OMe, and X is O or S.
A group of 4-aryl-1-isopropyl-1,3-dioxolo[4,5-g]quinazolin-2(1H)-ones and thiones as shown below were reported to have antiinflammatory activity (J. Med. Chem. 25: 1110-1113 (1982)). 
where Xxe2x95x90O or S, R=3-F, 4-Me, 3-OMe, 2-NO2 and other substitutents
This invention is related to novel AMPA antagonists represented by Formulae I-III. 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, cyanoalkyl, alkanoylamidoalkyl, alkanoyloxyalkyl, azidoalkyl, alkenyloxyalkyl, or alkoxyalkyl;
R6 and R7 taken together to form a five or six membered carbocyclic or heterocyclic ring including xe2x80x94OCH2Oxe2x80x94, xe2x80x94OCH2CH2Oxe2x80x94, xe2x80x94Oxe2x80x94CF2xe2x80x94Oxe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2CH2xe2x80x94, xe2x80x94OCH2CH2xe2x80x94 or xe2x80x94N(R,)xe2x80x94COxe2x80x94Oxe2x80x94; R9 is optionally substituted lower alkyl;
R5 and R8 are independently selected from the group consisting of hydrogen, halogen, haloalkyl, aryl, heterocyclic, heteroaryl, alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, hydroxyalkyl, nitro, amino, cyano, alkanoylamido, hydroxy, thiol, alkanoyloxy, alkoxy, carboxy, carbonylamido or thioalkoxy;
Xxe2x95x90O or S;
Y is aryl or heteroaryl, including for example 
wherein R2 is H, alkyl, halo, amino, alkoxy, or nitro;
R3 and R4 taken together to form a five or six membered carbocyclic or heterocyclic ring including xe2x80x94OCH2Oxe2x80x94, xe2x80x94OCH2CH2Oxe2x80x94, xe2x80x94Oxe2x80x94CF2xe2x80x94Oxe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2CH2xe2x80x94, Oxe2x80x94CH2CH2xe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94Oxe2x80x94. xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, or Oxe2x80x94CHxe2x95x90CHxe2x80x94;
n is 0 or 1; and
z is 0 or 1.
Certain of the compounds of the present invention may exist as optical isomers, and the invention includes both the racemic mixtures of such optical isomers as well as the individual enantiomers.
Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate.
The invention relates to the discovery that certain of the novel compounds represented by formula I are antagonists of AMPA receptors. Therefore the invention is related to a method of treating, preventing or ameliorating neuronal loss associated with stroke, global and focal ischemia, CNS trauma, hypoglycemia and surgery, spinal cord trauma, neuronal damage associated with cardiac arrest; as well as treating or ameliorating neurodegenerative diseases including Alzheimer""s disease, amyotrophic lateral sclerosis, Huntington""s disease, Parkinson""s disease and Down""s syndrome; treating, preventing or ameliorating the adverse consequences of the overstimulation of the excitatory amino acids; treating, preventing or ameliorating anxiety, convulsions, acute and chronic pain, migraine headache, muscle spasm and inducing anesthesia; as well as treating or ameliorating glaucoma and retinitis and preventing opiate tolerance, comprising administering to an animal in need of such treatment an effective amount of the AMPA receptor antagonists of the present invention, or a pharmaceutically acceptable salt or prodrug thereof.
Thus the invention is directed to the novel AMPA receptor modulators as defined in Formulae I-III.
The invention is also directed to methods employing the novel AMPA receptor modulators of Formulae I-III as antagonists of AMPA receptors.
The invention is also directed to a pharmaceutical composition comprising an effective amount of the AMPA receptor antagonists for the treatment of neurodegenerative conditions, acute and chronic pain and as anticonvulsants.
The invention is also directed to method for treating, preventing or ameliorating neuronal damage following global and focal ischemia; and treating, preventing or ameliorating neurodegenerative conditions and convulsions. The invention is also directed to the treatment, prevention or amelioration of acute and chronic pain. In addition, the invention is directed to a method for cognition enhancement and the treatment, prevention or amelioration of schizophrenia.
The invention is also directed to novel methods for the preparation of the novel AMPA receptor modulators as defined in Formulae I-III.
The novel AMPA antagonists modulators are represented by previously defined Formulae (I-III). Preferred structures of the novel compounds are represented by Formulae IV-VIII. In particular, a preferred embodiment is represented by Formulae IV: 
or a pharmaceutically acceptable salt or prodrug thereof wherein R1-R8 are as defined previously with respect to Formula I.
Another preferred embodiment is represented by Formula V: 
or a pharmaceutically acceptable salt or prodrug thereof wherein R1-R5 and R8-R9 are as defined previously with respect to Formula I;
Yet another preferred embodiment is represented by Formulae VI: 
or a pharmaceutically acceptable salt or prodrug thereof wherein R1-R8 and z are as defined previously with respect to Formula II.
Yet another preferred embodiment is represented by Formula VII: 
or a pharmaceutically acceptable salt or prodrug thereof wherein R1-R8 and z are as defined previously with respect to Formula II.
Yet another preferred embodiment is represented by Formula VIII: 
or a pharmaceutically acceptable salt or prodrug thereof wherein R1-R8 are as defined previously with respect to Formula III.
Preferred Y groups are carbocyclic, heterocyclic, aryl, heteroaryl groups, and bicyclic fused heterocyclic, aryl or heteroaryl groups, each of which may be independently substituted by hydrogen, halo, haloalkyl, aryl, a fused carbocyclic group, a fused heterocyclic group, a carbocyclic group, a heterocyclic group, a heteroaryl group, C1-10 alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, alkanoyloxy, azido, alkoxy, carboxy, or alkylthio groups.
With respect to the formulae above:
Typical C6-14 aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.
Typical carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Typical halo groups include fluorine, chlorine, bromine and iodine.
Typical C1-10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups. Also contemplated is a trimethylene group substituted on two adjoining positions on the benzene ring of the compounds of the invention.
Typical C2-4 alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and sec-butenyl.
Typical C2-4 alkynyl groups include ethynyl, propynyl, butynyl, and 2-butynyl groups.
Typical aralkyl groups include any of the above-mentioned C1-10 alkyl groups substituted by any of the above-mentioned C6-14 aryl groups.
Typical aralkenyl groups include any of the above-mentioned C alkenyl groups substituted by any of the above-mentioned C6-14 aryl groups.
Typical aralkynyl groups include any of the above-mentioned C2-4 alkynyl groups substituted by any of the above-mentioned C6-14 aryl groups.
Typical carbocycloalkyl groups include any of the above-mentioned C1-10 alkyl groups substituted by any of the above-mentioned carbocyclic groups.
Typical haloalkyl groups include C1-10 alkyl groups substituted by one or more fluorine, chlorine, bromine or iodine atoms, e.g. fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl and trichloromethyl groups.
Typical hydroxyalkyl groups include C1-10 alkyl groups substituted by hydroxy, e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups.
Typical alkoxy groups include oxygen substituted by one of the C1-10 alkyl groups mentioned above.
Typical alkylthio groups include sulphur substituted by one of the C1-10 alkyl groups mentioned above.
Typical alkanoylamino groups include any C1-6alkanoyl substituted on nitrogen, e.g. acetamido, propionamido, butanoylamido, pentanoylamido, hexanoylamido as well as aryl-substituted C2-6 substituted acyl groups.
Typical alkanoyloxy groups include any C1-6 acyloxy groups, e.g. acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy and the like.
Typical heterocyclic groups include tetrahydrofuranyl, pyranyl, A piperidinyl, piperazinyl, pyrrolidinyl, imidazolindinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl and pyrazolinyl groups.
Typical heterocycloalkyl groups include any of the above-mentioned C1-10 alkyl groups substituted by any of the above-mentioned heterocyclic groups.
Typical heteroaryl groups include any one of the following which may be optionally substituted with one or more C1-10 alkyl, halo, or hydroxy groups: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, 5aH-carbazolyl, carbazolyl, xcex2-carbolinyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl phenoxazinyl groups, 1,4-dihydroquinoxaline-2,3-dione, 7-aminoisocoumarin, pyrido [1,2-a]pyrimidin-4-one, 1,2-benzoisoxazol-3-yl, 4-nitrobenzofurazan, benzimidazolyl, 2-oxindolyl and 2-oxobenzimidazolyl. Where the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, e.g. a pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide and the like.
Typical heteroaralkyl groups include any of the above-mentioned C1-10 alkyl groups substituted by any of the above-mentioned heteroaryl groups.
Typical heteroaralkenyl groups include any of the above-mentioned C2-4 alkenyl groups substituted by any of the above-mentioned heteroaryl groups.
Typical heteroaralkynyl groups include any of the above-mentioned C2-4 alkynyl groups substituted by any of the above-mentioned heteroaryl groups.
Typical amino groups include xe2x80x94NH2, xe2x80x94NHR20 and xe2x80x94NR2OR21 wherein R20 and R21 are independently C1-10 alkyl groups as defined above.
Typical carbonylamido groups are carbonyl groups substituted by NH2, xe2x80x94NHR20, and xe2x80x94NR2OR21 groups as defined above.
When the group is an amidino or guinidino group, any one of the nitrogen atoms may be substituted independently by hydrogen, C1-10 alkyl or aryl groups.
Optional substituents on the aryl, aralkyl, aryloxy, arylthioxy, aroyl, heterocyclic, heterocycloxy, heteroaryl, heteroaryloxy, cycloalkyl, and cycloalkoxy groups listed above include any one of the typical halo, haloalkyl, aryl, fused heterocyclic, fused carbocyclic, heterocyclic, heteroaryl, C1-10 alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, cyano, alkanoylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, and alkylthiol groups mentioned above.
Preferred groups for R1 are C1-10 alkyl, haloalkyl, a carbocyclic group, a heterocyclic group, alkenyl, alkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl and aminoalkyl. Preferred groups for Y are substituted and unsubstituted heterocyclic, carbocyclic, heteroaryl and aryl. Most preferred groups for R2 are substituted and unsubstituted fused bicyclic heterocyclic, carbocyclic, heteroaryl and aryl.
Exemplary preferred compounds of Formulae I-III include, without limitation:
4-phenyl-cyclopento[g]quinazolin-2(1H)-one,
1-ethyl-4-phenyl-cyclopento[g]quinazolin-2(1H)-one,
6,7-ethylenedioxy-4-phenylquinazolin-2(1H)-one,
6,7-ethylenedioxy-1-isopropyl-4-phenylquinazolin-2(1H)-one,
6,7-ethylenedioxy-1-ethyl-4-phenylquinazolin-2(1H)-one,
1-methyl-6,7-methylenedioxy-4-phenylquinazolin-2(1H)-one,
1-ethyl-6,7-methylenedioxy-4-phenylquinazolin-2(1H)-one,
1-isopropyl-6,7-methylenedioxy-4-phenylquinazolin-2(1H)-one,
1-benzyl-6,7-methylenedioxy-4-phenylquinazolin-2(1H)-one,
1-ethyl-6,7-methylenedioxy-4-(4-methoxyphenyl)quinazolin-2(1H)-one,
1-ethyl-6,7-methylenedioxy-4-(4-methylphenyl)quinazolin-2(1H)-one,
1-ethyl-4-(4-fluorophenyl)-6,7-methylenedioxyquinazolin-2(1H)-one,
4-(3-aminophenyl)-1-ethyl-6,7-methylenedioxyquinazolin-2(1H)-one,
4-(4-aminophenyl)-1-isopropyl-6,7-methylenedioxyquinazolin-2(1H)-one,
1-ethyl-4-(4-hydroxyphenyl)-6,7-methylenedioxyquinazolin-2(1H)-one,
1-ethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-ethyl-4-(3,4-ethylenedioxyphenyl)-6,7-methylenedioxyquinazolin-2(1H)-one,
1-ethyl-6,7-methylenedioxy-4-(4,5-methylenedioxy-2-nitrophenyl)quinazolin-2(1H)-one,
4-(2-amino-4,5-methylenedioxyphenyl)-1-ethyl-6,7-methylenedioxyquinazolin-2(1H)-one,
1-ethyl-6,7-methylenedioxy-4-(3,4-dimethoxyphenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
4-(3,4-ethylenedioxyphenyl)-1-isopropyl-6,7-methylenedioxyquinazolin-2(1H)-one,
1-ethyl-6,7-methylenedioxy-4-(2-naphthyl)quinazolin-2(1H)-one,
1-(3-pentyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-methylenedioxy-4-(2-naphthyl)quinazolin-2(1H)-one,
1-cyclopropylmethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-(2-diethylaminoethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-(2-propynyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-methylenedioxy-4-(4-dimethylaminophenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-(difluoromethylenedioxy)-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-ethylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-(2-dimethylaminoethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-methylenedioxy-4-(2,3-dihydro-5-benzopuranyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-methylenedioxy-4-(6-chloro-3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-methylenedioxy-4-(5-indanyl)quinazolin-2(1H)-one,
1-(2-morpholinoethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-methylenedioxy-4-(3,4-difluoromethylenedioxyphenyl)quinazolin-2(1H)-one,
1-(1-methyl-2-dimethylaminoethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-methylenedioxy-4-(3-quinolinyl)quinazolin-2(1H)-one,
1-(2-aminoethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-methylenedioxy-4-(5-benzoxazolyl)quinazolin-2(1H)-one,
1-isopropyl-4-(3,4-methylenedioxyphenyl)-8-methyl-7-oxo-oxazol [5,4-g]quinazolin-2(1H)-one,
1-(2-pyrrolidinoethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
2-(2-diethylaminoethoxy)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-methyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(1-hydroxy-1-methyl)ethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-ethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-benzyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(2-dimethylaminoethoxy)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-dimethylamino-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(2-diethylaminoethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(2-chloroethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(2-dimethylaminomethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(2-dimethylamino-1-methylethoxy)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(3-chloropropyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(2-aminoethoxy)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(3-aminopropyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-n-pentyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)-3-(N-oxide)-quinazoline,
2-(imidazol-1-yl)methyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)-2-(1,2,4-triazol-1-y l)methyl-quinazoline,
2-((1-methyl-2-imidazolyl)thio)methyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(imidazol-1-yl)ethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-iodomethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-acetoxymethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(2-morpholinoethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-piperazinomethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(2-pyrrolidinoethoxy)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
1-(2-dimethylaminoethyl)-6,7-methylenedioxy-4-(3,4-ethylenedioxyphenyl)quinazolin-2(1H)-one,
1-Isopropyl-4-(3,4-methylenedioxyphenyl)-8-methyl-7-oxo-oxazol[5,4-g]quinazolin-2(1H)-one,
1-Isopropyl-4-(3,4-methylenedioxyphenyl)-8-benzyl-7-oxo-oxazol[5,4-g]quinazolin-2(1H)-one,
1-Isopropyl-4-(3,4-methylenedioxyphenyl)-8-ethyl-7-oxo-oxazol[5,4-g]quinazolin-2(1H)-one,
1-Isopropyl-4-(2-naphthyl)-8-ethyl-7-oxo-oxazol[5,4-g]quinazolin-2(1H)-one,
1-Isopropyl-4-(3,4-methylenedioxyphenyl)-8-propyl-7-oxo-oxazol [5,4-g]quinazolin-2(1H)-one,
1-Isopropyl-4-(3,4-methylenedioxyphenyl)-7-oxo-oxazol[5,4-g]quinazolin-2(1H)-one,
6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline 3-oxide,
2-Chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline 3-oxide,
2-Ethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline 3-oxide,
2-Methyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline 3-oxide,
2-(1-Imidazolyl)methyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline 3-oxide,
6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)-2-(1-pyrrolidinyl)methylquinazoline 3-oxide,
2-Dimethylaminomethyl-4-(3,4-methylenedioxyphenyl)-6,7-methylenedioxyquinazoline-3-oxide,
2-Methylaminomethyl-4-(3,4-methylenedioxyphenyl)-6,7-methylenedioxyquinazoline 3-oxide,
2-[2-(Dimethylamino)ethyl]-4-(3,4-methylenedioxyphenyl)-6.7-methylenedioxy-1(2H)-phthalazinone,
2-ethyl-4-(3,4-methylenedioxyphenyl)-6,7-methylenedioxy-1(2H)-phthalazinone,
2-[2-(1-Imidazolyl)ethyl]-4-(3,4-methylenedioxyphenyl)-6,7-methylenedioxy-1 (2H)-phthalazinone,
4-(3,4-Methylenedioxyphenyl)-6,7-methylenedioxy-1(2H)-phthalazinone,
2-[2-(1-Piperidinyl)ethyl]-4-(3,4-methylenedioxyphenyl)-6,7-methylenedioxy-1(2H)-phthalazinone,
2-[2-(1-Pyrrolidinyl)ethyl]-4-(3,4-methylenedioxyphenyl)-6,7-methylenedioxy-1 (2H)-phthalazinone, and
2-[2-(ethoxycarbonyl)ethyl]-4-(3,4-methylenedioxyphenyl)-6,7-methylenedioxy-1(2H)-phthalazinone.
The compounds of the present invention may exist as optical isomers and the invention includes both the racemic mixtures of such optical isomers as well as the individual enantiomers that may be separated according to methods that are well known to those of ordinary skill in the art.
Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate.
Examples of prodrugs include esters or amides of Formulae I-III where R1-R4 is hydroxyalkyl or aminoalkyl, which may be obtained by reacting such compounds with an anhydride such as acetic anhydride, propionyl anhydride, succinic anhydride and the like.
The invention is also directed to a method for treating disorders responsive to the blockade of AMPA receptors in animals suffering thereof. Particular Preferred embodiments of compounds for use in method of this invention are represented by previously defined Formulae I-III. Exemplary preferred compounds that may be employed in this method of invention include, without limitation:
6,7-methylenedioxy-4-phenylquinazolin-2(1H)-one,
4-phenyl-cyclopento[g]quinazolin-2(1H)-one,
1-isopropyl-4-phenyl-cyclopento[g]quinazolin-2(1H)-one,
1-ethyl-4-phenyl-cyclopento[g]quinazolin-2(1H)-one,
6,7-ethylenedioxy-4-phenylquinazolin-2(1H)-one,
6,7-ethylenedioxy-1-isopropyl-4-phenylquinazolin-2(1H)-one,
6,7-ethylenedioxy-1-ethyl-4-phenylquinazolin-2(1H)-one,
1-methyl-6,7-methylenedioxy-4-phenylquinazolin-2(1H)-one,
1-ethyl-6,7-methylenedioxy-4-phenylquinazolin-2(1H)-one. 1-isopropyl-6,7-methylenedioxy-4-phenylquinazolin-2(1H)-one,
1-benzyl-6,7-methylenedioxy-4-phenylquinazolin-2(1H)-one,
1-ethyl-6,7-methylenedioxy-4-(4-methoxyphenyl)quinazolin-2(1H)-one,
1-ethyl-6,7-methylenedioxy-4-(4-methylphenyl)quinazolin-2(1H)-one,
1-ethyl-4-(4-fluorophenyl)-6,7-methylenedioxyquinazolin-2(1H)-one,
4-(3-aminophenyl)-1-ethyl-6,7-methylenedioxyquinazolin-2(1H)-one,
4-(4-aminophenyl)-1-isopropyl-6,7-methylenedioxyquinazolin-2(1H)-one,
1-ethyl-4-(4-hydroxyphenyl)-6,7-methylenedioxyquinazolin-2(1H)-one,
1-ethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-ethyl-4-(3,4-ethylenedioxyphenyl)-6,7-methylenedioxyquinazolin-2(1H)-one,
1-ethyl-6,7-methylenedioxy-4-(4,5-methylenedioxy-2-nitrophenyl)quinazolin-2(1H)-one,
4-(2-amino-4,5-methylenedioxyphenyl)-1-ethyl-6,7-methylenedioxyquinazolin-2(1H)-one,
1-ethyl-6,7-methylenedioxy-4-(3,4-dimethoxyphenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
4-(3,4-ethylenedioxyphenyl)-1-isopropyl-6,7-methylenedioxyquinazolin-2(1H)-one,
1-ethyl-6,7-methylenedioxy-4-(2-naphthyl)quinazolin-2(1H)-one,
1-(3-pentyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-methylenedioxy-4-(2-naphthyl)quinazolin-2(1H)-one,
1-cyclopropylmethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-(2-diethylaminoethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-(2-propynyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-methylenedioxy-4-(4-dimethylaminophenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-(difluoromethylenedioxy)-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-ethylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-(2-dimethylaminoethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-methylenedioxy-4-(2,3-dihydro-5-benzopuranyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-methylenedioxy-4-(6-chloro-3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-methylenedioxy-4-(5-indanyl)quinazolin-2(l 1H)-one,
1-(2-morpholinoethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-methylenedioxy-4-(3,4-difluoromethylenedioxyphenyl)quinazolin-2(1H)-one,
1-(1-methyl-2-dimethylaminoethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-methylenedioxy-4-(3-quinolinyl)quinazolin-2(1H)-one,
(2-aminoethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
1-isopropyl-6,7-methylenedioxy-4-(5-benzoxazolyl)quinazolin-2(1H)-one,
1-isopropyl-4-(3,4-methylenedioxyphenyl)-8-methyl-7-oxo-oxazol[5,4-g]quinazolin-2(1H)-one,
1-(2-pyrrolidinoethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one,
2-(2-diethylaminoethoxy)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-methyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(1-hydroxy-1-methyl)ethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline. 2-ethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-benzyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(2-dimethylaminoethoxy)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-dimethylamino-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(2-diethylaminoethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(2-chloroethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(2-dimethylaminomethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(2-dimethylamino-1-methylethoxy)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(3-chloropropyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(2-aminoethoxy)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(3-aminopropyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-n-pentyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)-3-(N-oxide)-quinazoline,
2-(imidazol-1-yl)methyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)-2-(1,2,4-triazol-1-yl)methyl-quinazoline,
2-((1-methyl-2-imidazolyl)thio)methyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(imidazol-1-yl)ethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-iodomethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-acetoxymethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(2-morpholinoethyl)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-piperazinomethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
2-(2-pyrrolidinoethoxy)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline,
1-(2-dimethylaminoethyl)-6,7-methylenedioxy-4-(3,4-ethylenedioxyphenyl)quinazolin-2(1H)-one,
1-Isopropyl-4-(3,4-methylenedioxyphenyl)-8-methyl-7-oxo-oxazol[5,4-g quinazolin-2(1H)-one,
1-Isopropyl-4-(3,4-methylenedioxyphenyl)-8-benzyl-7-oxo-oxazol[5,4-g]quinazolin-2(1H)-one,
1-Isopropyl-4-(3,4-methylenedioxyphenyl)-8-ethyl-7-oxo-oxazol[5,4-g]quinazolin-2(1H)-one,
1-Isopropyl-4-(2-naphthyl)-8-ethyl-7-oxo-oxazol[5,4-g]quinazolin-2(1H)-one,
1-Isopropyl-4-(3,4-methylenedioxyphenyl)-8-propyl-7-oxo-oxazol[5,4-g]quinazolin-2(1H)-one,
1-Isopropyl-4-(3,4-methylenedioxyphenyl)-7-oxo-oxazol[5,4-g]quinazolin-2(1H)-one,
6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline 3-oxide,
2-Chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline 3-oxide,
2-Ethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline 3-oxide,
2-Methyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline 3-oxide,
2-(1-Imidazolyl)methyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline 3-oxide,
6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)-2-(1-pyrrolidinyl)methylquinazoline 3-oxide,
2-Dimethylaminomethyl-4-(3,4-methylenedioxyphenyl)-6,7-methylenedioxyquinazoline-3-oxide,
2-Methylaminomethyl-4-(3,4-methylenedioxyphenyl)-6,7-methylenedioxyquinazoline 3-oxide,
2-[2-(Dimethylamino)ethyl]-4-(3,4-methylenedioxyphenyl)-6,7-methylenedioxy-1(2H)-phthalazinone,
2-ethyl-4-(3,4-methylenedioxyphenyl)-6,7-methylenedioxy-1(2H)-phthalazinone,
2-[2-(1-Imidazolyl)ethyl]-4-(3,4-methylenedioxyphenyl)-6,7-methylenedioxy-1 (2H)-phthalazinone,
4-(3,4-Methylenedioxyphenyl)-6,7-methylenedioxy-1(2H)-phthalazinone,
2-[2-(1-Piperidinyl)ethyl]-4-(3,4-methylenedioxyphenyl)-6,7-methylenedioxy-1 (2H)-phthalazinone,
2-[2-(1-Pyrrolidinyl)ethyl]-4-(3,4-methylenedioxyphenyl)-6,7-methylenedioxy-1(2H)-phthalazinone, and
2-[2-(ethoxycarbonyl)ethyl]-4-(3,4-methylenedioxyphenyl)-6,7-methylenedioxy-1(2H)-phthalazinone.
The compounds of this invention may be prepared using methods well known to those skilled in the art, or by the novel methods of this invention. Specifically, compounds with Formula I can be prepared as illustrated by exemplary reactions in Scheme 1. 
Compounds with Formula I (Xxe2x95x90S) can be prepared as illustrated by exemplary reactions in Scheme 2. 
Compounds with Formula II can be prepared as illustrated by exemplary reactions in Scheme 3. 
Compounds with Formula I and II (R1 is dimethylaminoethyl) can be prepared as illustrated by exemplary reactions in Scheme 4. 
Alternatively, compounds with Formula II (R1=alkyl; n=z=0) can be prepared as illustrated by exemplary reactions in Scheme 5. 
Compounds with Formula II (z=1) can be prepared as illustrated by exemplary reactions in Scheme 6. 
Compounds with Formula III (z=1) can be prepared as illustrated b-exemplary reactions in Scheme 7. 
(a) PPTS, Acetone, H2O, reflux, 77%; (b) n-Bu4, Py, 54%; (c) H2NNH2H2O, EtOH reflux, 70%; (d) 
K2CO3, DMF, 80xc2x0 C., 91%; 16%; 81%; 91%; 55% (e) ethyl bromoacetate, K2CO3, DMF, 80xc2x0 C., 60%
The compounds of the present invention may be assessed by electrophysiological assays in Xenopus oocytes expressing rat whole brain poly(A)+ RNA (see Keana et. al. J. Med. Chem. 38: 4367-4379 (1995)) or in cultured rat cortical neurons (see Woodward et. al. Mol. Pharmacol. 47: 568-581 (1995)) for AMPA receptor activity. Compounds which are useful for treating or preventing the adverse consequences of stroke, hypoglycemia, neurodegenerative disorders, anxiety, epilepsy or psychosis, or which induce analgesia, will inhibit the currents across the membranes of the oocyte expressing AMPA receptors. However, if the compound potentiates currents across the oocyte membrane, then the compound is expected to be useful in enhancing cognition or treating schizophrenia or neurodegenerative disease such as Parkinson""s Disease.
The compounds of the present invention are active in treating, preventing or ameliorating neuronal loss, neurodegenerative diseases, acute and chronic pain, are active as anticonvulsants and inducing anesthesia. They are also useful for treating or ameliorating epilepsy and psychosis.
Neurodegenerative diseases which may be treated or ameliorated with the compounds of the present invention include those selected from the group consisting of Alzheimer""s disease, amyotrophic lateral sclerosis, Huntington""s disease, Parkinson""s disease and Down""s syndrome.
The compounds of the present invention find particular utility in the treatment of global and focal ischemia or prevention of neuronal loss associated with multiple strokes which give rise to dementia. After a patient has a cardiac arrest, the compounds of the present invention may be administered to ameliorate the ischemia related neuronal damage that may occur from cardiac arrest and other causes of global ischemia.
The compounds of the invention find particular utility in treating, preventing or ameliorating the adverse neurological consequences of surgery. For example, coronary bypass surgery requires the use of heart-lung machines Which tend to introduce air bubbles into the circulatory system which may lodge in the brain. The presence of such air bubbles robs neuronal tissue of oxygen, resulting in anoxia and ischemia. Pre- or post-surgical administration of the compounds of the present invention will treat or prevent the resulting ischemia. In a preferred embodiment, the compounds of the invention are administered to patients undergoing cardiopulmonary bypass surgery or carotid endarterectomy surgery.
The compounds of the present invention also find utility in treating, preventing or ameliorating acute and chronic pain. Such acute and chronic pain may be the result of surgery, trauma, headache, diabetes, arthritis, pain from terminal cancer or degenerative diseases. The compounds of the present invention also find particular utility in the treatment of phantom pain that results from amputation of an extremity. In addition to treatment of pain, the compounds of the invention are also expected to be useful in treating muscle spasm and inducing anesthesia, either general or local anesthesia, for example, during surgery.
The compounds of the present invention may be tested for in vivo anticonvulsant activity after iv or ip injection using a number of anticonvulsant tests in mice (audiogenic seizure model in DBA-2 mice, pentylenetetrazol-induced seizures in mice, maximum electroshock seizure test (MES)).
The compounds may be tested for their neuroprotective activity after focal and global ischemia produced in rats or gerbils according to the procedures described in Buchan et. al. (Stroke, Suppl. 148-152 (1993)), Sheardown et. al. (Eur. J. Pharmacol. 236:347-353 (1993)), and Graham et. al. (J. Pharmacol. Exp. Therap. 276:1-4 (1996)).
The compounds may be tested for their neuroprotective activity after traumatic spinal cord injury according to the procedures described in Wrathall et. al. (Exp. Neurology 137: 119-126 (1996)) and Iwasaki et. al. (J. Neuro Sci. 134:21-25 (1995)).
The compounds may also be tested in drug discrimination tests in rats trained to discriminate PCP from saline. It is expected that most of the compounds of the present invention will not generalize to PCP at any doses. In addition, it is also expected that none of the compounds will produce a behavioral excitation in locomotor activity tests in the mouse.
Elevated levels of glutamate have been associated with glaucoma. In addition, it has been disclosed that glaucoma management, particularly protection of retinal ganglion cells, can be achieved by administering to a patient a compound capable of reducing glutamate-induced excitotoxicity in a concentration effective to reduce the excitotoxicity. See WO94/13275. Thus, the compounds of the present invention, which are expected to cross the blood-retina barrier, are also expected to be useful in the treatment or amelioration of glaucoma. Preferably, the invention is directed to the treatment of patients which have primary open-angle glaucoma, chronic closed-angle glaucoma, pseudoexfoliation, or other types of glaucoma or ocular hypertension. Preferably, the compound is administered over an extended period (e.g. at least six months and preferably at least one year), regardless of the changes in the patient""s intraocular pressure over the period of administration.
The compounds of the present invention show potent activity in vivo after intraperitoneal injection suggesting that these compounds can penetrate the blood/brain barrier and are systemically bioavailable.
Thus, the present invention is directed to substituted quinazolines and analogs having preferred binding to AMPA receptors. According to the present invention, those compounds having preferred binding to AMPA receptors exhibit an IC50 of about 100 xcexcM or less in the electrophysiological assay. Preferably, the compounds of the present invention exhibit an IC50 of 10 xcexcM or less. Most preferably, the compounds of the present invention exhibit an IC50 of about 1.0 xcexcM or less.
The efficacy of the AMPA antagonists to inhibit glutamate neurotoxicity in rat brain cortex neuron cell culture system may be determined according to Choi, D. W., J. Neuroscience 7:357 (1987).
The anticonvulsant activity of the AMPA antagonists may be evaluated in the Maximal Electroshock-induced Seizure (MES) test. Seizures are induced by application of current (50 mA, 60 pulses/sec, 0.8 sec pulse width, 1 sec duration, d.c.) through saline-coated corneal electrodes using a Ugo Basile ECT device (Model 7801). Mice are restrained by gripping the loose skin on their dorsal surface, electrodes were held lightly against the two cornea, then current was applied and mice were observed for a period of up to 30 sec for the occurrence of a tonic hindlimb extensor response. A tonic seizure is defined as a hindlimb extension in excess of 90 degrees from the plane of the body. Results are treated in a quintal manner.
The anticonvulsant efficacy of the AMPA antagonists may also be assessed in the pentylenetetrazol (PTZ)-induced seizure test according to U.S. Pat. No. 5,514,680.
It is known that AMPA receptors are critically involved in pain transmission and the development of persistent pain following nerve and tissue injury. The effects of the AMPA receptor antagonists of the present invention on pain may be evaluated according to U.S. Pat. No. 5,514,680. The compounds of the present invention are useful in treating headaches, in particular, migraine headaches.
The anxiolytic activity of any particular compound described herein may be determined by use of any of the recognized animal models for anxiety. A preferred model is described by Jones, B. J. et al., Br. J. Pharmacol. 93:985-993 (1988).
Compositions within the scope of this invention include all compositions wherein the compounds of the present invention are contained in an amount which is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is with the skill of the art. Typically, the compounds may be administered to mammals, e.g. humans, orally at a dose of 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated for psychosis or anxiety disorders, e.g., generalized anxiety disorder, phobic disorders, obsessional compulsive disorder, panic disorder, and post traumatic stress disorders. Preferably, about 0.01 to about 10 mg/kg is orally administered to treat or prevent such disorders. For intramuscular injection, the dose is generally about one-half of the oral dose. For example, for treatment or prevention of anxiety, a suitable intramuscular dose would be about 0.0025 to about 15 mg/kg, and most preferably, from about 0.01 to about 10 mg/kg.
In the method of treatment or prevention of neuronal loss in global and focal ischemia, brain and spinal cord trauma, hypoxia, hypoglycemia, status epilepsy and surgery, the compound can be administrated by intravenous injection at a dose of 0.025 to 10 mg/kg. For the treatment of AIDS associated neuronal damage, Alzheimer""s disease, amyotrophic lateral sclerosis, Huntington""s disease and Down""s Syndrome, or in a method of treating a disease in which the pathophysiology of the disorder involves hyperactivity of the excitatory amino acids (e.g. convulsions) or AMPA receptor-ion channel related neurotoxicity, the pharmaceutical compositions of the invention may comprise the compounds of the present invention at a unit dose level of about 0.01 to about 50 mg/kg of body weight, or an equivalent amount of the pharmaceutically acceptable salt thereof, on a regimen of 1-4 times per day. When used to treat acute and chronic pain, to induce anesthesia, or to treat or prevent glaucoma, migraine headache, muscle spasm or urinary incontinence, the compounds of the invention may be administered at a unit dosage level of from about 0.01 to about 50 mg/kg of body weight, or an equivalent amount of the pharmaceutically acceptable salt thereof, on a regimen of 1-4 times per day. Of course, it is understood that the exact treatment level will depend upon the case history of the animal, e.g., human being, that is treated. The precise treatment level can be determined by one of ordinary skill in the art without undue experimentation.
The unit oral dose may comprise from about 0.01 to about 50 mg, preferably about 0.1 to about 10 mg of the compound. The unit dose may be administered one or more times daily as one or more tablets each containing from about 0.1 to about 10, conveniently about 0.25 to 50 mg of the compound or its solvates.
In addition to administering the compound as a raw chemical, the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically. Preferably, the preparations, particularly those preparations which can be administered orally and which can be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from about 0.01 to 99 percent, preferably from about 0.25 to 75 percent of active compound(s), together with the excipient.
Also included within the scope of the present invention are the non-toxic pharmaceutically acceptable salts of the compounds of the present invention. Acid addition salts are formed by mixing a solution of the particular AMPA antagonist of the present invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and the like. Basic salts are formed by mixing a solution of the particular AMPA antagonist of the present invention with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like.
The pharmaceutical compositions of the invention may be administered to any animal which may experience the beneficial effects of the compounds of the invention. Foremost among such animals are mammals, e.g., humans, although the invention is not intended to be so limited.
The pharmaceutical compositions of the present invention may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal routes. Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
The pharmaceutical preparations of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropymethyl-cellulose phthalate, are used. Dye stuffs or pigments, may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.
Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400). Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers.
The characterization of non-competitive AMPA receptors antagonists in vitro has been difficult because of the lack of selective drug ligands. Thus, the AMPA ligands of the present invention may be used to characterize the AMPA receptors and their distribution. Particularly preferred AMPA antagonists and positive modulator of the present invention which may be used for this purpose are isotopically radiolabelled derivatives. e.g. where one or more of the atoms are replaced with 3H, 11C, 14C, 15N, or 18F. Alternatively, a fluorescent group Yxe2x80x2 may be employed. Examples of such groups include 4-nitrobenzofurazan.
The following examples are illustrative, but not limiting, of the method and compositions of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the invention.